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WO2001021164A2 - Compositions anti-mycobacterium, procedes de preparation et d'utilisation associes - Google Patents

Compositions anti-mycobacterium, procedes de preparation et d'utilisation associes Download PDF

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WO2001021164A2
WO2001021164A2 PCT/US2000/026196 US0026196W WO0121164A2 WO 2001021164 A2 WO2001021164 A2 WO 2001021164A2 US 0026196 W US0026196 W US 0026196W WO 0121164 A2 WO0121164 A2 WO 0121164A2
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composition
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pyridin
mycobacterium
alkyl
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WO2001021164A3 (fr
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Yuh-Meej Lin
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Advanced Life Sciences Inc
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Advanced Life Sciences Inc
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Priority to EP00963753A priority patent/EP1217995A2/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to methods and compositions for preventing or treating mycobacte ⁇ um infections, particularly tuberculosis infections 0
  • Infectious diseases remain the largest cause of death m the world toda . greater than cardiovascular disease or cancer '
  • tuberculosis is the leading cause of death 2 5
  • Tuberculosis caused by the infection of Mvcobactenum tuberculosis (Mtb), kills three million people worldwide and eight million people develop the disease each year according to current estimates by the World Health Organization (WHO) More people die from TB than from mala ⁇ a. diarrhea.
  • WHO World Health Organization
  • Tuberculosis mainly affects the lungs but can also involve other organs TB st ⁇ kes 0 people of all ages, but is more common among the elderly
  • the disease can also afflict animals, especially livestock such as cattle, hogs and poultry
  • This disease once ranked among the most common causes of death in the world
  • MDRTB multidrug-resistant tuberculosis
  • TB amplified bv the global HIV pandemic
  • TB infection is a se ⁇ ous problem for acquired immunodeficiency syndrome (AIDS) - ⁇ patients
  • AIDS -infected individuals are particularly susceptible to infection with Mtb and the development of TB
  • an individual n ec e w as a mes.gre v . n an n v ua n ec e w .
  • HIV the presence of other infections, including TB, may allow HIV to multiply more quickly. This may result in more rapid progression of HIV infection and AIDS. 6
  • CD4+ lymphocytes decline in number and function. The immune system is less able to prevent the growth and local spread of Mtb.
  • pulmonary TB is still the most common form of TB.
  • the presentation of the disease depends on the degree of immunosuppression.
  • the natural history of TB in a child infected with HIV depends on the stage of HIV disease.
  • Early in HIV infection when immunity is strong, the signs of TB are similar to those in a child without HIV infection.
  • dissemination of TB becomes more common and tuberculous meningitis, miliary tuberculosis, and widespread tuberculous lymphadenopathy occur more frequently.
  • Isoniazid isonicotinic acid hydrazide
  • Isoniazid was first reported to be effective against Mtb and M. bovis in 1952. 8"10 Isoniazid, now still a front-line therapy against TB, has been shown to be an effective prophylactic antitubercular 11 , and modern short-course chemotherapy is initiated with three drugs: isoniazid, rifampin and pyrazinamide (PZA), often with the inclusion of a fourth drug, usually ethambutol.
  • PZA pyrazinamide
  • rifapentine a derivative of rifamycin, was approved by the FDA for the treatment of tuberculosis.
  • Drug resistance resulting from inadequate treatment, such as irregular drug supply, inappropriate regimens or poor compliance is a potential threat to TB control programs throughout the world.
  • Patients infected with strains resistant to multiple drugs are less likely to be cured, particularly if they are infected with HIV or malnourished, and their treatment is more toxic and more expensive than the treatment of patients with susceptible organisms.
  • the present invention relates to compounds, compositions and methods for treating and/or preventing mycobacterium infections, especially tuberculosis infections, in patients.
  • the method is useful for treating or preventing mycobacterium infections in immunocomprised patients, particularly HIV infected patients.
  • the present invention relates to compounds, compositions and methods for the prevention or treatment of mycobacterium infections.
  • the compounds are naturally occurring and synthetic biflavonoids, flavonoids, chalcones and chalcone like compounds.
  • the compounds were screened for anti-mycobacterium activity and several were found to cause inhibition of a mycobacterium infection. Of these, eight were identified as particularly potent, exhibiting greater than 90 % inhibition of the growth of Mtb at a concentration of 12.5 ⁇ g/mL.
  • the actual minimum inhibitory concentrations (MIC), defined as the lowest concentration inhibiting 99% of the inoculum, for the preferred compounds ranged from 6.8 to 48.3 ⁇ M.
  • one object of the invention is a method for preventing or treating a mycobacterium infection in a mammal comprising administering to a mammal in need of anti- mycobacterium prevention or treatment an effective anti-mycobacterium amount of at least one compound of formula /.
  • R ⁇ -R 9 are independently comprised of H; OCH 3 ; EtO; OH; O-alkenyl; phenyl; NH 2 ; COOH; F; Cl; Br; I; CONH 2 ; NO 2 ; NR 10 Rn OCONRioRn wherein R, 0 and R n independently comprise H alkyl (e.g., C ⁇ - 6 linear or branched alkyl) or aryl (e.g., unsubstituted phenyl or phenyl substituted with one or more of the following: C 1- alkyl, C ⁇ -6 alkoxy, hydroxy-Cl-4 alkyl, hydroxyl, amino, C ⁇ -6 alkylamino, di(C ⁇ - alkyl)amino, amino-C ⁇ -8 alkyl, C 1-8 alkylamino-C 1-8 alkyl, di(C ⁇ -6 alkyl)amino-C ⁇ -8 alkyl, nitro, azido or halogen
  • Another object of the invention is a method for preventing or treating a mycobacterium infection in a mammal comprising administering to a mammal in need of anti-mycobacterium prevention or treatment an effective anti-mycobacterium amount of at least one compound of formula ii.
  • R comprises pyridin-3-yl-, phenanthren-9-yl-, phenanthren-9-yl-, phenyl-, 2- aminopyridino-3-yl, 2-aminopyridino-3-yl-, pyridin-2-yl-, phenyl-, 4-dimethyl-aminophenyl-, furan-2-yl-, indol-2-yl-, furan-2-yl-, 2-aminopyridin-3-yl-, 4-dimethylaminophenyl-, furan-2- yl-, pyridin-4-yl-, pyridin-3-yl-, 2-aminopyridin-3-yl-, 2-aminopyridin-3-yl-, 2-aminopyridin- 3-yl-, pyridin-4-yl- or 4-methoxyphenyl-; or a pharmaceutically acceptable derivative or salt thereof.
  • Another object of the invention is a method for preventing or treating a mycobacterium infection in a mammal comprising administering to a mammal in need of anti-mycobacterium prevention or treatment an effective anti-mycobacterium amount of at least one compound of formula Hi.
  • Rj-R 8 are independently comprised of H; OCH 3 ; EtO; OH; O-alkenyl; phenyl; NH 2 ; COOH; F; Cl; Br; I; CONH 2 ; NO 2 ; NR 10 Rn OCONR 10 R U wherein R 10 and R assume independently comprise H alkyl (e.g., Cj- 6 linear or branched alkyl) or aryl (e.g., unsubstituted phenyl or phenyl substituted with one or more of the following: C 1-6 alkyl, C 1-6 alkoxy, hydroxy-Cl-4 alkyl, hydroxyl, amino, C ⁇ -6 alkylamino, di(C ⁇ -6 alkyl)amino, amino-C 1-8 alkyl, C 1-8 alkylamino-C 1-8 alkyl, di(C ⁇ -6 alkyl)amino-C ⁇ - alkyl, nitro, azido or halogen); COR 1 where
  • R J comprises alkyl (e.g., C 6 linear or branched alkyl) or aryl (e.g., unsubstituted phenyl or phenyl substituted with one or more of the following: C ⁇ -6 alkyl, C 1-6 alkoxy, hydroxy-Cl-4 alkyl, hydroxyl, amino, C ⁇ -6 alkylamino, di(C ⁇ -6 alkyl)amino, amino-C ⁇ -8 alkyl, C ⁇ -8 alkylamino-C ⁇ - alkyl, di(C ⁇ _ 6 alkyl)amino-C 1-8 alkyl, nitro, azido or halogen); OAc; benzoyl;
  • Another object of the invention is a method for preventing or treating a mycobacterium infection in a mammal comprising administering to a mammal in need of anti-mycobacterium prevention or treatment an effective anti-mycobacterium amount of at least one compound of formula iv.
  • R ⁇ -R 8 are independently comprised of H; OCH 3 ; EtO; OH; O-alkenyl; phenyl; NH 2 ; COOH; F; Cl; Br; I; CONH 2 ; NO 2 ; NR 10 R ⁇ OCONR 10 Rn wherein R 10 and Rn independently comprise H alkyl (e.g., C ⁇ - 6 linear or branched alkyl) or aryl (e.g., unsubstituted phenyl or phenyl substituted with one or more of the following: C 1- alkyl, C ⁇ - alkoxy, hydroxy-Cl-4 alkyl, hydroxyl, amino, C ⁇ -6 alkylamino, di(C 1-6 alkyl)amino, amino-C ⁇ - alkyl, C 1-8 alkylamino-C ⁇ -8 alkyl, di(C ⁇ -6 alkyl)amino-C 1-8 alkyl, nitro, azido or halogen); COR ⁇ 2 wherein
  • 1-6 . alkyl C 1-6 alkoxy, hydroxy-Cl-4 alkyl, hydroxyl, amino, C ⁇ -6 alkylamino, di(C ⁇ -6 alkyl)amino, amino-C ⁇ -8 alkyl, C ⁇ -8 alkylamino-C ⁇ - alkyl, di(C ⁇ -6 alkyl)amino-C ⁇ -8 alkyl, nitro, azido or halogen); OAc; benzoyl; CONH ; or NO ; or pharmaceutically acceptable derivative or salt thereof.
  • Yet another object of the invention is a method for treating or preventing mycobacterium infection in a patient comprising biflavonoid compounds, particularly 6-6"- biapigenin hexamethylether, volkensiflavone hexamethylether, GB-la hexamethylether, 3'"- Nit O-C3-O-C4"'-biflavone, 3'-8"-biflavone, 6-2'"-biflavone, 6-6"-binaringenin hexamethylether or 6-2'"-biapigenin or derivative or salt thereof and pharmaceutically acceptable carriers therefor.
  • biflavonoid compounds particularly 6-6"- biapigenin hexamethylether, volkensiflavone hexamethylether, GB-la hexamethylether, 3'"- Nit O-C3-O-C4"'-biflavone, 3'-8"-biflavone, 6-2'"-biflavone
  • Still yet another object of the invention is to provide anti-mycobacterium composition
  • biflavonoid compounds for treating or preventing a mycobacterium infection in a patient particularly 6-6"-biagpigenin hexamethylether, volkensiflavone hexamethylether, GB- la hexamethylether, 3"'-Nitro-C3-O-C4 m -biflavone, 3'-8"-biflavone, 6-2'"-biflavone, 6-6"- binaringenin hexamethylether or 6-2'"-biapigenin or derivative or salt thereof and pharmaceutically acceptable carriers therefor.
  • This invention relates to compounds, compositions and methods for treating or preventing mycobacterium infections in mammals.
  • the compounds of the present invention are synthetic or naturally occurring chalcones, chalcone-like compounds, biflavonoids and flavonoids.
  • the compounds were screened for anti-mycobacterium activity. Of the compounds showing anti- mycobacterium activity, eight were identified as particularly potent, exhibiting greater than 90 % inhibition of the growth of Mtb at a concentration of 12.5 ⁇ g/mL.
  • the preferred compounds of this invention which exhibited greater than 90 % inhibition of the growth Mtb at a concentration of 12.5 ⁇ g/mL, were chalcone-like compounds (heterocyclic ring substituted 2-propen-l-one) l-(4-fluorophenyl)-3-(pyridin-3-yl)-2-propen-l- one (53) (98%), l-(3-hydroxyphenyl)-3- ⁇ henanthren-9-yl-2-propen-l-one (54) (97%), l-(5- pyridin-2-yl)-3-(phenanthen-9-yl)-2-propen-l-one (55) (96%), and l-(furan-2-yl)-3-phenyl-2- propen-1-one (56) (96%); chalcones l-(2-hydroxyphenyl)-3-(3-chlorophenyl)-2-propen-l-one (24) (90%) and l-(2-hydroxyphenyl)-3-(
  • MIC minimum inhibitory concentrations
  • the compounds and compositions of the present invention can be used to treat or prevent mycobacterium infections.
  • Representative mycobacterial organisms include Mycobacterium avium complex (MAC), Mycobacterium kansaii, Mycobacterium marinum, Mycobacterium phlei, Mycobacterium ulcerans, Mycobacterium xenopi, Mycobacterium gordonae, Mycobacterium terrae complex, Mycobacterium haemophilum, Mycobacterium fortuitum, Mycobacterium tuberculosis, Mycobacterium laprae, Mycobacterium scrofulaceum and Mycobacterium smegmatis.
  • the compounds and compositions are particularly useful in treating Mycobacterium tuberculosis infections.
  • the compounds of the invention may be formulated as a solution of lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation is generally a buffered, isotonic, aqeuous solution.
  • suitable diluents are normal isotonic saline solution, standard 5% dextrose in water or in buffered sodium or ammonium acetate solution.
  • Such formulation is especially suitable for parenteral administration, but may also be used for oral administration.
  • excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium choride or sodium citrate.
  • the compounds of the present invention may be encapsulated, tableted or prepared in an emulsion (oil-in-water or water-in-oil) syrup for oral administration.
  • Pharmaceutically acceptable solids or liquid carriers which are generally known in the pharmaceutical formulary arts, may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Solid carriers include starch (corn or potato), lactose, calcium sulfate dihydrate, terra alba, croscarmellose sodium, magnesium stearate or stearic acid, talc, pectin, acacia, agar, gelatin, maltodextrins and microcrystalline cellulose, or colloidal silicon dioxide.
  • Liquid carriers include syrup, peanut oil, olive oil, com oil, sesame oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or g ycery s eara e, a one or w a w . u , , _ between about 10 mg to about 1 g per dosage unit.
  • an anti-mycobacterium effective amount for treating or preventing a mycobacterium infection refers to the amount administered so as to maintain an amount which suppresses or inhibits mycobacterium infection as evidenced by standard assay.
  • the dosage will also be determined by the existence of any adverse side effects that may accompany the compounds. It is always desirable, whenever possible, to keep adverse side effects to a minimum.
  • One skilled in the art can easily determine the appropriate dosage, schedule, and method of administration for the exact formulation of the composition being used in order to achieve the desired effective concentration in the individual patient.
  • the dosage can vary from between about 0.001 mg/kg/day to about 50 mg/kg/day, but preferably between about 0.01 to about 1.0 mg/kg/day.
  • the following examples are illustrative of the invention but does not serve to limit its scope.
  • NMR and 13 C-NMR spectra were recorded on a Varian XL300 NMR spectrometer in CDC1 , DMSO-d 6 or acetone-d 6 as specified using TMS as an internal standard. Chemical shifts are expressed in parts per million ( ⁇ , ppm).
  • IR spectra were recorded using a Midac FT-IR spectrometer, with samples being prepared as KBr pellets, or using a Perkin-Elmer spectrum 1000 FT-IR.
  • Mass spectral data were recorded using a Finnegan MAT 90 mass spectrometer.
  • Analytical thin-layer chromatography (TLC) was carried out on precoated plates (silica gel F 5 from EM Science). Column chromatography was performed with silica gel 60 (70-230 mesh from EM Science). The structures of compounds were confirmed by their TLC profiles as well as their IR, NMR and MS spectra.
  • Chalcones and chalcone-like compounds were prepared by base- catalyzed condensation of appropriately substituted ketones with substituted benzaldehydes or - . substituted benzaldehyde in alcohol was added a 60% solution of potassium hydroxide dropwise with stirring. The reaction mixture was kept at 0°C for 2 days, then diluted with water and acidified with acetic acid. The precipitated chalcone was collected and recrystalized from alcohol to yield pure chalcone. 15 ' 16
  • Flavones were synthesized by treating the corresponding chalcones, prepared by the method described above, with selenium dioxide in amyl alcohol. Thus, 2'-, 3'- and 4'- monohalogenoflavones were prepared as usual by condensation of hydroxyacetophenone with -, m- and /?-halogenobenzaldehydes to provide chalcones. This was followed by cyclization of the chalcones with selenium dioxide in amyl alcohol. 17"19 6-Fluoro-, 6-chloro- and 6- bromoflavones and related compounds were prepared from 2-hydroxy-5- halogenoacetophenones. 19
  • Flavonols were prepared by treating the corresponding chalcones with a 16% solution of aqueous sodium hydroxide and a 15% solution of hydrogen peroxide (v/v 1:1). The 6- halogenoflavonols were prepared in good yield by cyclization of the corresponding chalcones in cold alkaline hydrogen peroxide. 20 ' 21
  • Flavanones were prepared by refluxing the corresponding chalcones with phosphoric acid in alcohol for 2-3 days. Generally, 2-hydroxy-5-halogenoacetophenones condensed smoothly with benzaldehyde or -anisaldehyde in the presence of alcoholic alkali, giving chalcones, which were cyclized in phosphoric acid to obtain 6-halogenoflavanones.
  • Naturally occurring biflavanoids amentoflavone, agathisflavone, robustaflavone, hinokflavone, rhusflavanone, succedaneaflavanone, volkensiflavone, morelloflavone and GB- . - biflavonoids were synthesized by Ulman condensation of monohalogeno flavones.
  • 6, 6" -Biapigenin hexamethylether (MCR 408, 151/ 6,6"-Biapigenin hexamethylether (151) was synthesized by a three-step synthesis from 4,4'-dibenzyloxy-2,2',6,6'- tetrarnefhoxybiphenyl, which was prepared from the Ullmann reaction of benzyl 4-iodo-3,5- dimethoxyphenyl ether.
  • Volkensiflavone hexamethylether (MCR360, 152). Volkensiflavone hexamethyl-ether was prepared from volkensiflavone, which was isolated from the methanol extract of Garcinia multiflora.
  • volkensiflavone The dried heartwood of Garcinia multiflora (shavings, 3 kg) was extracted with boiling methanol (4 times). The extract was evaporated to yield a brown oily material, which was extracted with toluene to remove oily substances. The insoluble part was extracted with ethyl acetate. The ethyl acetate extract yielded a light brown solid (25 g) which was chromatographed on 500 g of silica gel, eluting with toluene-ethyl acetate (1 :2) to provide fractions I (4 g), II (0.3 g) and III (1.7 g).
  • Fraction I was further chromatographed on a column of polyamide (nylon 66, 200 g), eluting with 70% aqueous methanol to provide fractions la (0.1 g), lb (0.6 g), Ic (0.35 g) and Id (0.5 g). Recrystallization of fraction Id with ethyl acetate/methanol yielded 0.3 g of volkensiflavone as a yellow powder.
  • volkensiflavone 200 mg was dissolved in 20 mL of dry acetone and 2.5 mL of dimethylsulfate and 2 g of potassium carbonate were added. The solution was refluxed for 4 hr, and then filtered. The filtrate was concentrated and purified by silica gel column chromatography using a mixture of toluene and ethyl acetate in a ratio of 1:2 . - and concentrated to leave an ivory solid which was recrystallized from a solvent mixture of chloroform and methanol to obtain volkensiflavone hexamethylether as colorless crystals, 138 mg, m.p.
  • the screening was conducted at a drug concentration of 12.5 ⁇ g/mL against Mtb H38Rv in BACTEC 12B medium using a BACTEC 460 radiometric system.
  • the assay procedure was carried out according to the method described previously. 39 Compounds were solubilized in dimethylsulfoxide at 1 mg/mL and sterilized by passage through 0.22 ⁇ m PFTE filters. A volume of 50 ⁇ L was added to 4 mL BACTEC 12B medium (Becton Dickinson) to achieve a final concentration of 12.5 ⁇ g/mL. Approximately 4 x 105 colony forming units of M. tuberculosis H37Rv (ATCC 27294) were added and the cultures were incubated at 37 °C.
  • the percent inhibition was calculated as 1 - (test sample GI ⁇ control GI) x 100.
  • the test compounds and results are summarized in Tables 1-5.
  • the activity of 2'-hydroxychalcone (61% inhibition) was enhanced by introducing a chloro or a methoxyl group at the 4'-position of the A-ring, e.g. compound 25 (89%), and 1 (78%>), while a bromo, or a iodo substituent at the 4'-position of the B-ring led to a decrease in activity, e.g. 35 (57%) and 21 (45%).
  • the effect of a substituent at the 4'-position of the A-ring of 2'-hydroxy chalcone for anti-TB activity was Cl [25 (89%)] > OCH 3 [1 (78%)] > no substituent [5 (61%)] > Br [35 (57%)] > I [21 (45%)].
  • the common structural feature of these four compounds is that they all have a heterocyclic ring or a phenyl ring with a hydrophilic group substituent on one side of the molecule, and an aromatic ring, such as phenyl or phenanthrenyl, with or without a hydrophobic substituent on the other side.
  • Additional hydrophylic substituents such as methoxyl, hydroxyl and amino groups resulted in dramatic decrease or complete loss of activity. From the above results, active compounds resulted from structures having a lipophilic group on one side and a hydrophilic group on the other side of the 2-propen- 1 -one core template.
  • flavones The anti-TB activities of flavones are presented in Table 3. All flavones tested, including carboxylated, halogenated, hydroxylated and methoxylated flavones were only moderately to weakly active or inactive, while halogenated flavones or halogenated flavonols (3 -hydroxy flavones) demonstrated moderate activity.
  • Flavones with bromine or chlorine substitution at the 8-position displayed inhibitory activity against Mtb with 66% and 62% growth inhibition at a dose of 12.5 ⁇ g/mL, respectively, while the flavones with a halogen substitution at the 3-position (compound 127), 6-, 7-, or 8-position of ring A (compounds 102, 105, 106, 112, 114, 122, 123 and 124) and 2', 3', or 4'-position of ring B (compounds 84, 97, 99, 100, 101, 111 and 121) were weakly active or inactive. Flavonol (3-hydroxyflavone) (92) exhibited weak activity of 38% inhibition.
  • Flavanones g een avanones were eva ua e or an - ac v y. e resu s are s e n a e
  • 5-Methoxy-8-bromoflavanone (133) demonstrated the most significant activity among these flavanones, with 87% inhibition against Mtb.
  • the substitution of a bromo group on the B-ring demonstrated higher activity than that on the A-ring [3'-bromo- (134), 73%, versus 7-bromo- flavanone (136), 53%].
  • Biflavonoid methylethers constructed with two flavone units or with a flavone and a flavanone unit displayed equal strength of activity (151 and 152).
  • a biflavonoid methylether (153) constructed with two flavanone units demonstrated less activity than that constructed with a flavone and a flavanone (152) (87% versus 95% inhibition), although both compounds have the same linkage structure (13 -118).
  • Biapigenin hexamethylether with a linkage of 13-113 (159) was completely devoid of activity. This result indicated that the 16-116 linkage might be important for the activity.
  • Rhusflavanone hexaacetate (173): R COMe
  • chalcone compounds 24 and 40
  • four chalone like compounds heterocyclic ring substituted 2-propen- 1 -ones
  • the common structural features of these six compounds are that all the compounds have two aromatic rings, one ring substituted with a heteroatom and the other with or without hydrophobic substitutions. Introduction of extra hydrophilic substituents such as methoxyl, hydroxyl and amino groups would render the compounds less active.
  • compound 53 the other five compounds all have a hydrogen-bonding group substituted on the A-ring, while the B-ring remained hydrophobic.
  • Structural superposition analysis indicateed that compound 53 can actually be superimposed on the other five compounds the other way.
  • compound 53 can superimpose its A-ring with the B- ring of compound 56, while keeping its B ring superimposed with the A ring of compound 56 (Scheme 2).
  • Flavones and flavanones can be viewed as geometrically constrained chalcone analogues. It may indeed be due to these structural constraints that they are less active compared to chalcones.
  • Some examples illustrate the relationship of activity between a chalcone and its corresponding flavone, i.e., when a chalcone was converted to its corresponding flavone, the anti-TB activity decreased.
  • Examples of this include compound 44 being converted to compound 100 in which activity decreased from 41% to 22%; 44 to 100, 41% to 22%; 31 to 99, 83% to 23%; 33 to 97, 70% to 26%, 24 to 121, 90% to 0%; and 27 to 111, 67% to 7%.
  • the only exception to this pattern was compound 46 being converted to compound 84 (21% to 51%).
  • flavones are less active, and are structurally more restricted, with the two terminal aromatic rings in the same plane.
  • the structures of the biflavonoids are apparently different from that of chalcone and flavanoid monomers.
  • the two active biflavonoids have only methoxyl substitutions (a methoxyl group is not a good hydrogen bonding group), while the chalcone and chalcone-like compounds prefer a hydroxyl or other
  • Halogenoflavonoids III Synthesis of 2'- , 3'-, 4'-, 6-Bromofiavanones and 6-Bromo-fiavones. J. Formosan Sci. 1953, 7, 57-62.
  • Chen, F.C., Lin, C, Lai, S.C. Synthesis of Halogenoflavonoids IV. Synthesis of 2'-,3'-, 4'-Iodoflavanone and Corresponding Chalcones. J. Formosan Sci. 1953, 7, 63-65.

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Abstract

L'invention concerne des composés, compositions et procédés de prévention ou traitement d'infections à Mycobacterium. Ces composés sont des biflavonoïdes, flavonoïdes, chalcones ou des composés de type chalcone, naturels ou synthétiques, criblés pour leur activité anti-Mycobacterium. Parmi des composés possédant une telle activité, on en a identifié huit qui sont particulièrement puissants et démontrent un pourcentage d'inhibition, supérieur à 90 %, de la croissance de Mtb à une concentration de l'ordre de 12,5 $g8m)µg/m. Pour les composés préférés, les concentrations minimales réelles d'inhibition, déterminées comme étant les concentrations les plus faibles inhibant 99 % de l'inoculum, se situaient entre 6,8 et 48,3 νµM.
PCT/US2000/026196 1999-09-22 2000-09-22 Compositions anti-mycobacterium, procedes de preparation et d'utilisation associes Ceased WO2001021164A2 (fr)

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AU38853/01A AU3885301A (en) 1999-09-22 2000-09-22 Anti-mycobacterium compositions and methods of preparing and using same
EP00963753A EP1217995A2 (fr) 1999-09-22 2000-09-22 Compositions anti-mycobacterium, procedes de preparation et d'utilisation associes

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US15551999P 1999-09-22 1999-09-22
US60/155,519 1999-09-22
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EP1764363A3 (fr) * 2005-09-15 2007-05-16 Riemser Arzneimittel AG Derives d'acetophenone substitues
US7329687B2 (en) 2002-04-18 2008-02-12 Sri International Flavanoid compounds as chemotherapeutic, chemopreventive, and antiangiogenic agents
KR100830541B1 (ko) * 2006-08-11 2008-05-21 충남대학교산학협력단 인터루킨-5 저해효과를 갖는 신규 찰콘계 유도체
WO2008155393A1 (fr) * 2007-06-20 2008-12-24 Centre National De La Recherche Scientifique (Cnrs) Utilisation d'hétérocycles oxygénés choisis parmi les xanthones et les biflavonoïdes pour la préparation d'une composition destinée à agir comme agent anti-coccidien
US7638554B2 (en) 2002-04-18 2009-12-29 Sri International Flavanoids as chemotherapeutic, chemopreventive, and antiangiogenic agents
AU2006233256B2 (en) * 2006-10-30 2012-01-19 Armaron Bio Pty Ltd Improved flavonols
EP2468741A1 (fr) 2010-12-16 2012-06-27 Bel/Novamann International s.r.o. Nouveaux dérivés de quercetin, leur procédé de préparation, les compositions pharmaceutiques qui les contiennent et leur utilisation
CN103087025A (zh) * 2013-02-22 2013-05-08 天津科技大学 次生代谢活性成分穗花杉双黄酮的全合成方法
CN103864742A (zh) * 2012-12-13 2014-06-18 天津科技大学 一类新颖柚皮素衍生制备及抗肿瘤应用
WO2016021695A1 (fr) * 2014-08-06 2016-02-11 国立大学法人 群馬大学 Agent antibactérien
WO2017013239A1 (fr) * 2015-07-22 2017-01-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Activateurs de nrf2 pour le traitement d'infections mycobactériennes
JP2018131454A (ja) * 2010-07-27 2018-08-23 トラスティーズ オブ ボストン ユニバーシティ 新規癌治療法としてのアリール炭化水素受容体（ＡｈＲ）改変物質
CN109620827A (zh) * 2018-12-14 2019-04-16 中国医学科学院医药生物技术研究所 杂环丙烯酮类化合物作为抗菌剂的用途

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EP3215149A4 (fr) 2014-11-06 2018-06-27 Northwestern University Inhibition de la motilité de cellules cancéreuses
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US7638554B2 (en) 2002-04-18 2009-12-29 Sri International Flavanoids as chemotherapeutic, chemopreventive, and antiangiogenic agents
US7329687B2 (en) 2002-04-18 2008-02-12 Sri International Flavanoid compounds as chemotherapeutic, chemopreventive, and antiangiogenic agents
WO2005016907A1 (fr) * 2003-07-16 2005-02-24 Centre National De La Recherche Scientifique Nouveau derives de flavones, leur procede de preparation et compositions pharmaceutiques les contenant
FR2857665A1 (fr) * 2003-07-16 2005-01-21 Centre Nat Rech Scient Nouveaux derives de flavones, leur procede de preparation et compositions pharmaceutiques les contenant
EP1764363A3 (fr) * 2005-09-15 2007-05-16 Riemser Arzneimittel AG Derives d'acetophenone substitues
KR100830541B1 (ko) * 2006-08-11 2008-05-21 충남대학교산학협력단 인터루킨-5 저해효과를 갖는 신규 찰콘계 유도체
AU2006233256B2 (en) * 2006-10-30 2012-01-19 Armaron Bio Pty Ltd Improved flavonols
FR2917621A1 (fr) * 2007-06-20 2008-12-26 Centre Nat Rech Scient Utilisation d'heterocycles oxygenes choisis parmi les xanthones et les biflavonoides pour la preparation d'une composition destinee a agir comme agent anti-coccidien
WO2008155393A1 (fr) * 2007-06-20 2008-12-24 Centre National De La Recherche Scientifique (Cnrs) Utilisation d'hétérocycles oxygénés choisis parmi les xanthones et les biflavonoïdes pour la préparation d'une composition destinée à agir comme agent anti-coccidien
JP2018131454A (ja) * 2010-07-27 2018-08-23 トラスティーズ オブ ボストン ユニバーシティ 新規癌治療法としてのアリール炭化水素受容体（ＡｈＲ）改変物質
EP2468741A1 (fr) 2010-12-16 2012-06-27 Bel/Novamann International s.r.o. Nouveaux dérivés de quercetin, leur procédé de préparation, les compositions pharmaceutiques qui les contiennent et leur utilisation
CN103864742A (zh) * 2012-12-13 2014-06-18 天津科技大学 一类新颖柚皮素衍生制备及抗肿瘤应用
CN103087025A (zh) * 2013-02-22 2013-05-08 天津科技大学 次生代谢活性成分穗花杉双黄酮的全合成方法
WO2016021695A1 (fr) * 2014-08-06 2016-02-11 国立大学法人 群馬大学 Agent antibactérien
JP2016037456A (ja) * 2014-08-06 2016-03-22 国立大学法人群馬大学 抗菌剤
WO2017013239A1 (fr) * 2015-07-22 2017-01-26 INSERM (Institut National de la Santé et de la Recherche Médicale) Activateurs de nrf2 pour le traitement d'infections mycobactériennes
CN109620827A (zh) * 2018-12-14 2019-04-16 中国医学科学院医药生物技术研究所 杂环丙烯酮类化合物作为抗菌剂的用途
CN109620827B (zh) * 2018-12-14 2021-01-19 中国医学科学院医药生物技术研究所 杂环丙烯酮类化合物作为抗菌剂的用途

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